HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination

BACKGROUND: Multiple sclerosis (MS) in the pediatric age group is being increasingly recognized. In adults, complex interactions between genetic and environmental factors contribute to risk and the major genetic component of MS susceptibility localizes to the major histocompatibility complex (human leukocyte antigen [HLA]). Whether HLA alleles predict MS in at-risk children presenting with acquired demyelinating syndromes (ADS) of the CNS is unknown. METHODS: HLA-DRB1 alleles were typed using an allele-specific PCR amplification method on samples from 266 children presenting with ADS enrolled in the prospective Canadian Pediatric Demyelinating Disease Study and from 196 healthy controls. RESULTS: Sixty-four of 266 children with ADS met established criteria for a diagnosis of MS during a mean follow-up of 3.2 ± 1.5 years. Children harboring DRB1*15 alleles were more likely to be diagnosed with MS (χ(2) = 12.2, p < 0.001; OR = 2.7), an observation strengthened by children of European ancestry (χ(2) = 10.5, p = 0.001; OR = 3.3). DRB1*15 allele frequencies in children with ADS of European ancestry subsequently diagnosed with MS were greater than in children with monophasic ADS (χ(2) = 10.7, p = 0.001) or healthy controls (χ(2) = 12.5, p < 0.001). The proportion of children with non-European ancestry diagnosed with MS was not influenced by DRB1*15 status. CONCLUSION: DRB1*15 alleles confer increased susceptibility to pediatric-onset MS, supporting a fundamental similarity in genetic contribution to MS risk in both pediatric- and adult-onset disease. The specificity of the DRB1*15 risk allele for children with subsequent MS diagnosis, but not for all children with ADS, indicates that the risk conveyed by DRB1*15 relates to chronic CNS disease (MS), rather than acquired demyelination in general

MHC transmission: Insights into gender bias in MS susceptibility

OBJECTIVE: Major histocompatibility complex (MHC) genes dominate genetic susceptibility factors in multiple sclerosis (MS). Given the general consensus that incidence and prevalence of MS has been rising and specifically in women, we evaluated MHC-gender interactions. METHODS: In a large family-based cohort consisting of 7,093 individuals (2,127 affected individuals) from 1,055 MS families, we examined MHC transmission by family structure and gender stratified by genetic distance of affected relatives from the MS proband. RESULTS: We found that affected individuals with HLA-DRB1*15-positive genotypes have higher female-to-male ratios as compared with affected individuals with HLA-DRB1*15-negative genotypes (χ(2) = 9.97, p = 0.0015) with the exception of multiplex families with 3 or more affected across 2 generations. Transmission disequilibrium test results show that HLA-DRB1*15 transmission was more distorted in collateral families vs nuclear families (χ(2) = 8.030, p = 0.0046), exclusively in affected female-female pairs (χ(2) = 7.81, p = 0.0051), but not in mixed gender pairs (χ(2) = 1.58, p = 0.21) or matched male pairs (Fisher p = 0.21). CONCLUSIONS: These observations implicate the MHC as the site of interactions and modifications mediating the female-to-male gender ratio in MS and its progressive increase. They further suggest this occurs via gene-environment interactions and epigenetic modifications in this region. The difference between collateral and nuclear families provides some insight into the inheritance, decay, and gender specificity of putative epigenetic marks